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Disparate results in studies of methotrexate plus corticosteroids in the treatment of giant cell arteritis: Comment on the article by Hoffman et al

2003; Wiley; Volume: 48; Issue: 4 Linguagem: Inglês

10.1002/art.10867

1529-0131

Juan Ángel Jover, César Hernández-Garcı́a, Inmaculada C. Morado, Emilio Vargas, Antonio Bañares, Benjamín Fernández‐Gutiérrez,

Coagulation, Bradykinin, Polyphosphates, and Angioedema

We read with interest the report of the multicenter study on the use of adjuvant methotrexate (MTX) therapy in giant cell arteritis (GCA), by Dr. Hoffman and the International Network for the Study of Systemic Vasculitides (INSSYS) (1). The main conclusion from this work was that the use of MTX as an adjunct to prednisone therapy was not justified to control disease activity or to decrease the cumulative dose and toxicity of corticosteroids in patients with GCA. As Hoffman et al comment on extensively in their Discussion section, we have recently published the results of a randomized, double-blind, placebo-controlled trial showing that the combination of MTX and prednisone was more efficient than prednisone alone in maintaining disease remission, allowing lower prednisone requirements over a 2-year period (2). In our opinion, the differing results of the 2 studies might be explained by differences in patient selection, duration of followup, and steroid therapy. We do not believe differences in the definition of relapses have a significant role in the differences in outcomes. Our definition of relapse did not include change in the erythrocyte sedimentation rate (ESR) and was based exclusively on "recurrence of symptoms of giant-cell arteritis after definite objective improvement followed by symptom reversal upon resumption of or increases in the prednisone dose." This definition, in accordance with Hoffman and colleagues' study, excluded isolated elevation of ESR as a criterion for relapse. In addition, although elevation of ESR was not included as a requisite for the definition of a relapse, all relapses in both the MTX and the placebo groups were in fact accompanied by elevations in ESR. In our opinion, definition and management of relapses were, with small methodologic differences, quite similar in the 2 studies, and it is unlikely that the difference in results lies therein. Patient selection could make a difference. While a positive biopsy result was required for inclusion in our study, the INSSYS study included patients (up to 17%) without a positive biopsy result, raising the possibility that patients with GCA-like conditions could have been included in the study. Furthermore, the selection process in Hoffman et al's study is unclear: no data are provided regarding the total number of eligible patients, the proportion of eligible patients who were randomized, causes for nonrandomization, or the proportion of patients in each of the 17 participating centers. This makes it difficult to rule out some sort of selection bias. Although the difference in relapse incidence at 1 year was not statistically significant between groups, a detailed analysis of the results of the INSSYS study reveals a diminished cumulative incidence of each of the specific symptoms of GCA, except tongue or jaw pain, in the MTX group; this achieved statistical significance for both polymyalgia rheumatica and sustained fever. This divergence between clinical findings and statistical results might be caused by the recalculation of the study sample (initially set at 300, and then changed to 84). After the recalculation, the authors determined that a difference in the relapse rate of ≥50% would be necessary for statistical power to be maintained. This is higher than the difference found in our study (39%). Had Hoffman et al preserved the initial sample size, a difference of only 25% in the relapse rate would have become statistically significant. Two other factors might help in the understanding of their results, the first being a followup period of only 12 months, making the possibility of detecting long-term differences in outcomes impossible. The second factor is that, by study design, a second relapse was considered as a definite treatment failure, which prevented some patients from having their MTX adjusted to a higher, and eventually more efficacious, weekly dosage. We think both factors are relevant and might have important consequences in terms of the statistical results, especially in view of survival curves for relapses and treatment failures, which demonstrate a positive effect of MTX. Finally, we believe the most relevant factor that might explain the relative lack of efficacy of MTX in Hoffman et al's study is the alternate-day corticosteroid regimen, compared with the daily schedule used in our study. Although an alternate-day corticosteroid regimen has shown some success in several autoimmune conditions (3-7), its use in GCA is not widespread, and its efficacy in this disease was shown by Hunder et al to be low (8). In that study, 14 of 20 GCA patients had a relapse after 4 weeks of alternate-day therapy, while this occurred in only 2 of 20 patients receiving daily therapy. Supporting the contention that alternate-day corticosteroid therapy has suboptimal efficacy in GCA is the fact that a significant percentage of patients in Hoffman and colleagues' study developed ischemic visual symptoms after initiation of therapy, while in our study (2) and the study by Spiera et al (9), using different daily regimens of prednisone alone or with MTX, no patient developed this complication. Taken together, the results of the 3 recent studies on GCA and MTX (1, 2, 9) indicate that the treatment of patients should be based on high initial doses of corticosteroids and a tapering daily schedule. The use of MTX as adjuvant therapy permits faster steroid withdrawal and a lower cumulative corticosteroid dose, while achieving good disease control. The choice between the use of MTX or a more conservative corticosteroid-tapering schedule should be based on careful weighing of the risks and benefits of each option in individual patients. Juan Angel Jover MD, PhD*, Cesar Hernández-Garcia MD*, Inmaculada C. Morado MD*, Emilio Vargas MD, PhD*, Antonio Bañares MD, PhD*, Benjamin Fernandez-Gutierrez MD, PhD*, * Hospital Clínico San Carlos, Madrid, Spain.